IE63232B1 - A process for the preparation of 5-acylamino-2,4,6-triiodo- or tribromo-benzoic acid derivatives and corresponding novel 5-acylamino-2,4,6-triiodo or tribromo-benzoic acid derivatives obtained by said process - Google Patents

A process for the preparation of 5-acylamino-2,4,6-triiodo- or tribromo-benzoic acid derivatives and corresponding novel 5-acylamino-2,4,6-triiodo or tribromo-benzoic acid derivatives obtained by said process

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IE63232B1
IE63232B1 IE151888A IE151888A IE63232B1 IE 63232 B1 IE63232 B1 IE 63232B1 IE 151888 A IE151888 A IE 151888A IE 151888 A IE151888 A IE 151888A IE 63232 B1 IE63232 B1 IE 63232B1
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formula
bis
group
triiodo
alkyl
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IE151888A
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IE881518L (en
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Ernst Felder
Carlo Musu
Luciano Fumagalli
Fulvio Uggeri
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Bracco Int Bv
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Priority claimed from IT20647/87A external-priority patent/IT1205029B/en
Priority claimed from IT8847935A external-priority patent/IT1219934B/en
Application filed by Bracco Int Bv filed Critical Bracco Int Bv
Publication of IE881518L publication Critical patent/IE881518L/en
Publication of IE63232B1 publication Critical patent/IE63232B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

PCT No. PCT/EP88/00453 Sec. 371 Date Oct. 10, 1989 Sec. 102(e) Date Oct. 10, 1989 PCT Filed May 20, 1988 PCT Pub. No. WO88/09328 PCT Pub. Date Dec. 1, 1988.A process for the preparation of 5-acylamino-2,4,6-triiodo or tribromo-benzoic acid derivatives of formula (I), wherein X is I or Br, R is H or a variously substituted alkyl, or a group of formula (II), wherein X has the above meanings; Y is hydroxy, alkoxy, hydroxyalkoxy, alkylamino or hydroxyalkylamino; Z may be the same as COY or it is hydroxylalkylaminocarbonyl provided that at least one of the two acyl or R groups is hydroxy-substituted, which process comprises the rearrangement of the corresponding 5-(alkylaminocarbonyl-alkoxy)-2,4,6-trioodo ro tribromo-benzoic acid derivatives, in the presence of bases.

Description

A PROCESS FOR THE PREPARATION OF 5-ACYLAMINO-2,4,6-TRIIODO- OR TRIBROMO-BENZOIC ACID DERIVATIVES AND CORRESPONDING NOVEL 5-ACYLAMINQ-2,4,6-TRIIODO OR TRIBROMO-BENZOIC ACID DERIVATIVES OBTAINED BY SAID PROCESS.
The invention relates to a new synthetic process, particularly suited for the preparation · of 5-acylamino-2,4,6-triiodo or tribromo-benzoic acid derivatives of formula I ς CO - Y X 1 X 10 Acyl^ N / R V X z I. wherein : X is I or Br, with the proviso that all are the same Acyl is a C -C hydroxyalkanoy1, alkoxyalkanoy1 or alkoxy-hydroxyalkanoyl group or a C^-C^ unsubstit.uted alkanoyl group, R is H or a C -C alkyl, hydroxyalkyl, alkoxyalkyl or 6 alkoxy-hydroxyalkyl group, or a H(OCH^CH), Me (OCH CH ) - or Et(OCH CH ) - group, or a 2 2-4 2 2 2-4 group of formula X wherein X, Y, Z and Acyl have the same meanings as in formula I and Alkylene- is a straight or branched C^-C^ alkylene group, which in turn may be substituted by hydroxy groups and/or interrupted by 0,S, SO or SO2, is a hydroxy, alkoxy, hydroxyalkoxy, alkylamino group or preferably a hydroxyalkylamino group of formula -N Alkyl(OH) n wherein R is H or a C -C^ alkyl, hydroxyalkyl, alkoxyalkyl or alkoxy-hydroxyalkyl group, Alkyl is a straight or branched alkyl group and n = 1, 2 or 3, Z may have the same meaning of CO-Y in formula I or may be a hydroxyalkylaminocarbonyl group of formula Z -CON ^AlkyKOH) n wherein R, Alkyl and n are as above defined or Z may also be a C -C acylamino, hydroxyacy1amino, 2 5 N-aIky 1-acylamino, N-hydroxyalkylacylamino or acylaminomethyl group, with the proviso that at least one of the two Acyl or R groups is hydroxy substituted, said process being characterized in that corresponding 5-( alkylaminocarbony 1-alkoxy )-2,4 ,6-tri iodo or benzoic ac 1 a deri vat ives of formula t. r ibromoII, or -(acylami no-a1koxy)-2,4,6-triiodo or tr ibromo-benzo ic X Acyl—NH-CH -CH-0 Z I u R, wherein: 1 X and Y have the same meanings as in formula I, Z' may be the same as Z in formula I, but. it. may also be a group of formula R'-NH-CO-CH-OI Ri or Acyl-NH-CH2-CH-OR' wherein R', R and Acyl are as hereinbelow defined, is H or a C -C alkyl, hydroxyalkyl, alkoxyalkyl or 1 6 alkoxy-hydroxyalkyl group or a Me(OCH CH ) 2 2 2-4 group of formula H(°CH2CH2'2-5· or group, or a O-CH-CO-NH- AlkyleneI R1 wherein X, Y, 1' are as above defined, R is as herein10 below defined, Alkylene- is a straight or branched C -C * · 2 8 alkylene group, which in turn may be substituted by hydroxy groups and/or interrupted by 0, S, SO or SO^, is H or a alkyl, hydroxyalkyl or alkoxyalkyl R.
Acyl C -C hydroxyalkanoyl, alkoxyalkanoy1 or 6 group, is a alkoxy-hydroxyalkanoy1 group or an unsubstituted C2~C^ alkanoyl group, are subjected, in presence of bases, to a rearrangement reaction to give the desired compounds of formula I.
The present invention also relates to 5-acylamino2,4,6-triiodo or tribromo-benzoic acid derivatives which, having never being disclosed so far, were for the first time obtained by the process described in the present invention .
Rearrangment reaction of II and/or respectively III into I is only formally analogous to Smiles rearrangement reaction (Smiles Rearrangement; The MERCK Index, Tenth Edition, Organic Name Reactions, pag. ONR-84) and may be represented as follows: II----> I: R '-NH-CO-CH-O-Ar------> HO-CH-CO-N ( R ' )-Ar III---* I: Ri Ri Acyl-NH-CH^-CH-O-Ar----> Acyl-N-CH^CH-OH R.
Ar wherein: R', and Acyl are as above defined and Ar is a trihalo substituted aromatic ring as defined in formula I.
Rearrangment takes place in presence of bases and, generally but not exclusively, at a temperature equal to or higher than room temperature, in order to increase the reaction rate. The equilibrium which takes place between compound II or III and compound I is often so shifted towards I that, by means of the process described in the present invention, yields even higher than 90% may be obtained.
Said process is of the greatest interest from the technical point of view since it makes it possible to obtain compounds of formula I, starting from easily available compounds such as the ether derivatives of -hydroxy-2,4,6-triiodo or tribromo-benzoic acid, said compounds of formula I being very interesting but generally more difficult to obtain in high yields, according to the known methods.
Compounds of formula I are valuable components of contrast agents in radiology.
Among these, particularly useful are some -( N-acyl-amino )-2 , 4,6-t.r i iodo or t-r ibromo-bi s-( hydroxyalkyl ) isophthalamide derivatives, since they are non-ionic contrast agents endowed with good tolerability and high water-solubility. Ionic contrast agents used hitherto, are being replaced to a higher and higher extent by this new class of products, since it has a lot of outstanding advantages in particular as far as tolerability is concerned.
As in no way limitative examples of non-ionic contrast agents used in radiology, which may be prepared according to the process described in the present invention, the following compounds are hereinbelow reported; * * Iopamidol = (S) N, N '-bis/f2-hydroxy-l-(hydroxymethyl) ethy1/-5-/12-hydroxy-1-oxopropyl)aminc/-2,4,6-triiodo-1,3benzenedicarboxyamide; Ger. Pat. 2 547 789.
Iomeprol = N,N'-bis (2,3-dihydroxypropy1)-5-/7hydroxyacetyl)methylamino7-2,4,6-triiodo-1,3-benzenedicarboxyamide; Eur. Pat. 26 281.
Ioversol = N,N'-bis (2,3-dihydroxypropyl)-5-/7hydroxyacetyl)(2-hydroxyethyl)-amino/-2,4,6-triiodo-l,3-benzenedicarboxyamide; U.S.A. Pat. 4 396 598.
N,N'-bis/2-hydroxy-1-( hydroxymethyl)ethyl/-5-/T2-hydroxy-loxopropy1)methylamino7-2,4,6-tr i iodo-1,3-benzenedicarboxyamide; Eur. Pat. 26 281.
N,N'-b i s/2-hydroxy-1-( hydroxymethy 1)ethy1/-5-/fhydroxyacethyl)methylaminq7-2,4,6-triiodo-l,3-benzenedicarboxyamide; Eur. Pat. 26 281. 1.3- bis/N-(3,5-bis-(2 ,3-dihydroxypropylaminocarbonyl )-2,4,6 -tri iodo-phenyl )-N-hydroxyacetyl-amino7propane ; Eur. Pat.. 992. 1.4- bi s/N-(3,5-bis-(1,3-dihydroxy i sopropylami nocarbonyl ) 2,4,6-tri iodo-phenyl)-N-hydroxyacetylamino/2,3-dihydroxybu7 tane; Eur. Pat. 23 992.
The process of the invention also make it possible to prepare novel 5-acylamino-2, 4,6-triiodo or tribromo-benzoic acid derivatives which are part of the disclosure and are useful contrast agents in radiology.
The search for novel aromatic tri- or hexa- iodine or bromine derivatives which are water-soluble, well tolerable, non-ionic and useful as radio-opaque agents is so difficult that the achievement of a product fullfilling even only one of such requirements must already be considered as inventive and accordingly patentable.
Examples of new compounds which fullfill the above said requirements, and which were obtained according to the process object of the present invention, are hereinbelow reported: - 5-(N-2,3-dihydroxypropyl-N-hydroxyacetyl-amino)-2,4,6triiodo-bis-(2,3-dihydroxypropyl)isophthalamide; - 5-(N-2,3-dihydroxypropyl-N-hydroxyacetyl-amino)-2,4,6triiodo-bis-(1,3-dihydroxyisopropyl)isophthalamide; - 5 - (N-2,3-dihydroxypropyl-N- c< -hydroxypropionyl-amino ) 2 , 4,6-triiodo-bis-(2,3-dihydroxypropyl )isophthalamide; - 5-(N-2,3-dihydroxypropyl-N- -hydroxypropionyl-amino ) 2,4,6-tri iodo-bi s-(1,3-dihydroxy isopropyl)isophthalamide ; - 5-(N-1,3-dihydroxyi sopropy1-N-hydroxyacetyl-amino )-2,4,6tribromo-bis-(1,3-dihydroxyisopropyl)isophthalamide; - 5-(N-l,3-dihydroxy i sopropy1-N-hydroxyacety1-amino )-2,4,6tri iodo-b i s-(1,3-dihydroxyisopropyl)isophthalamide; - 5-( N-2-hydroxyethy 1-N--hydroxypropionyl-amino )-2,4,6triiodo-bis-(2,3,4-trihydroxy-1-butyl )isophthalamide; - 5-(N-2-hydroxyethyl-N-X -hydroxypropionyl-amino)-2,4,6tri iodo-bis-(1,3,4-trihydroxy-2-butyl)isophthalamide; - 5- (N-2-hydroxy-3-methoxypropyl-N-hydroxyacetyl-amino) 2,4, 6-triiodo-bis-(2,3-dihydroxypropyl)isophthalamide; - 5-(N-methy1-N-hydroxyacetyl-amino )-2,4,6,-tri iodo-bis(2,3,4-trihydroxy-l-butyl)isophthalamide; - 5-(N-methy1-N-hydroxyacetyl-amino)-2,4,6-tri iodo-bi s(1,3,4-trihydroxy-2-butyl)isophthalamide; - 5-(N-2 , 3,4-trihydroxy-l-butyl-N-hydroxyacetil)-2,4,6tri iodo-bis(2-hydroxyethyl)isophthalamide ; - 5-(N-methyl-N-hydroxyacetyl-amino)-2,4,6-triiodo-((N—2,3 — dihydroxypropyl)-(N *-2-hydroxyethyl))isophthalamide; - 5-(N-2,3-dihydroxypropy1-N-hydroxyacetyl-amino)-2,4,6tri iodo-bis(2,3-dihydroxyethyl) isophthalate; - 5-(N-methyl-N-hydroxyacetyl-amino)-2,4,6-triiodo-bis(1,3-dihydroxyisopropyl) isophthalate ; - l,3-bis-(N-(3,5-bis(l,3-dihydroxyisopropylaminocarbonyl) -2,4,6-tri iodo-phenyl)-N-hydroxyacetyl-amino) -2-hydroxypropane; - l,3-bis-(N-(3,5-bis(2,3-dihydroxypropylaminocarbonyl) 2.4.6- tri iodo-phenyl )-N-hydroxyacetyl-amino) -2-hydroxypropane; - l,6-bis-(N-(3,5-bis(2,3-dihydroxypropylaminocarbonyl ) 2.4.6- tr i iodo-phenyl)-N-hydroxyacety1-amino )-2,3,4,5tetrahydroxy-hexane; - l,7-bis-(N-(3,5-bis(l,3-dihydroxy isopropy laminocarbony 1) -2,4,6-tri iodo-phenyl )-N-hydroxyacetyl-amino)-2,6-dihydroxy-4-oxa-heptane; - l,5-bis-(N-(3,5-bis(2,3-dihydroxypropylami nocarbonyl) -2,4,6-t. ri iodo-ph enyl)-N-hydroxyacetyl- ami no )-3-thia9 pentane; - l,5-bis-(N-(3,5-bis(2,3-dihydroxypropylaminocarbonyl) 2,4,6-triiodo-phenyl)-N-hydroxyacetyl-amino)-3-thia-pentane-3-oxide; - l,5-bis-(N-(3,5-bis(2,3-dihydroxypropylaminocarbonyl) 2.4.6- triiodo-phenyl)-N-hydroxyacetyl-amino)-3-thia-pentane-3,3-dioxide; - l,3-bis-(N-(3-(2,3-dihydroxypropylaminocarbonyl)-5-(2-hydroxyethylaminocarbonyl )-2,4,6-triiodo-phenyl)-N-hydroxyacetyl-amino)-2,2-bis-(hydroxymethyl)-propane; - l,3-bis-(N-(3-(l,3-dihydroxyi sopropylaminocarbonyl )-5(2-hydroxyethylaminocarbonyl )-2,4,6-triiodo-phenyl)-Nhydroxyacetyl-amino)-2,2-bis-(hydroxymethyl)-propane; - 3,5-bis-(N-methyl-N-hydroxyacetyl-amino)-2,4,6-tri iodo(2,3-dihydroxypropyl)benzamide; - 3,5-bis-(N-methyl-N-hydroxyacetyl-amino)-2,4,6-triiodo(1,3-dihydroxyisopropyl) benzamide; - 3,5-bis-(N-methyl-N-o( -hydroxy propionyl-ami no )-2,4,6tri iodo-(1,3-dihydroxyisopropyl) benzamide; - 3,5-bis-(N-2-hydroxyethyl-N-hydroxyacety1-amino )-2,4,6triiodo-(2,3-dihydroxypropyl)benzamide; - 3,5-bis-(N - 2 - hydrox yet. hy 1 - N-hydroxyacety 1 - amino )-2,4,6tri iodo-(1,3-dihydroxyιsopropyl) benzamide; - 3,5-bis-(N-2-hydroxyet.hyl-N- - 3, 5-bis - (N-2-hydroxyethyl-N- c( -hyd roxypropi onyl-amino )2.4.6- triiodo-(1,3-dihydroxyi sopropyl) benzamide; - 3, 5-bis-(N-2-hydroxyethyl-N-hydroxyacetyl-amino )-2,4,6t r iiodo-(2-hydroxyethyl) benzamide; - 3,5-bis-(N-2-hydroxyethy1-N-hydroxyacety1-amino )-2,4,610 tri iodo-(N, N-bi s-(2-hydroxyethyl)) benzamide ; - 3,5-bis-(N-2-hydroxyethyl-N-hydroxyacetyl-amino )-2,4,6triiodo-(2-hydroxyethyl)benzoate; - 3,5-bis-(N-2-hydroxyethyl-N-hydroxyacetyl-amino )-2,4,6triiodo-(2,3-dihydroxypropyl) benzoate; - 3-(N-2-hydroxyethyl-N-hydroxyacetyl-amino)-5-acetylamino-2,4,6-tri iodo-(2,3-dihydroxypropyl) benzamide; - 3-(N-2-hydroxyethyl-N-hydroxyacetyl-amino)-5-(N-metyl-N acetyl-amino )-2,4,6-tri iodo-(2,3-dihydroxypropyl) benzamide; - 3-( N-2-hydroxyethyl-N-hydroxyacetyl-amino) -5-ace'tylami nomethy1-2,4,6-tri iodo-(2,3-dihydroxypropyl) benzamide; - 3-(N-2-hydroxyethyl-N-hydroxyacetyl-amino)-5-acetylaminomethyl-2,4,6-tri iodo-(2-hydroxyethyl) benzoate; - 5-(N-2-hydroxyethy1-N-hydroxyacetyl-amino)-2,4,6-triiodo-bis-(N,N-bis(2-hydroxyethyl))isophthalamide; - 5-(N-2,3-dihydroxypropy1-N-hydroxyacetyl-amino)-2,4,6triiodo-bis-(N,N-bis(2-hydroxyethyl))isophthalamide; - 5-(N-2-hydroxyethyl-N- -hydroxypropionyl-amino )-2,4,6triiodo-bis-(N,N-bis(2-hydroxyethyl))isophthalamide; - 5-(N-2-hydroxyethyl-N-hydroxyacetyl-amino )-2, 4, 6-triiodo-bis - ( N-2,3-dihydroxypropy1-N-2-hydroxyethy 1)isophthalamide; - 5-( N-2-hydroxy ethyl-N-hydroxy acetyl-ami no )-2,4,6-t. riiodo-bis-(N-1,3-dihydroxyisopropyl-N-2-hydroxyethy 1) isophthalamide; - 5-(N-methyl-N-hydroxyacetyl-ami no )-2,4,6-tri iodo-bi s-(N 1,3-dihydroxyisopropyl-N-2-hydroxyethyl)isophthalamide; - l,3-bis-(N-(3,5-bis-(N,N-bis(2-hydroxyethy1)aminocarbonyl) -2 , 4 , 6-tri iodo-phenyl) -N-hydroxyacetyl-amino)-211 hydroxy-propane; - 1, 3-bis-(N-( 3, 5-bis-(N,N-bis( 2-hydroxyet.hyl ) am i noca rbony 1)-2,4,6-tri iodo-phenyl )-N-hydroxyacet. yl-amino )propane; - 1, 3-bis-(N-( 3, 5-bis-(N,N-bis-( 2-hydroxyet.hyl ) aminocarbonyl)-?,4,6-tri iodo-phenyl)-N-hydroxyacetyl-amino)-2,2bis-( hydroxymethyl)-propane; - 1,4-bis-(N-(3,5-bis-(N,N-bis(2-hydroxvethyl) ami nocarbonyl) -2, 4 , 6-tri iodo-phenyl)-N-hydroxyacetyl-amino)-2,3dihydroxy-butane; - 1, 4-bis-(N-( 3, 5-bis-(N,N-bis( 2-hydroxyet.hyl ) ami nocarbonyl)-?,4,6-tri iodo-phenyl )-N--hydroxypropionyl-amino )-2,3-dihydroxy-butane; - 1,4-bis-(N-(3,5-bis-(N-l,3-dihydroxyi sopropyl-N-2-hydroxy ethyl-ami nocarbonyl )-2,4,6-t. ri iodo-phenyl ) - N-hydroxyacetyl-amino )-2,3-dihydroxy-butane; - 1,4-bis-(N-(3,5-bis-(N-l,3-dihydroxyisopropyl-N-2-hydroxyethyl-ami nocarbonyl )-2,4,6-t.riiodo-phenyl ) -N- -hydroxypropionyl-amino )-2, 3-dihydroxy-but ane: - 1, 5-bis-(N-( 3, 5-bis-(N,N-bis( 2-hydroxvet.hyl ) ami noca r bony 1 )-2,4,6-triiodo-phenyl)-N-hvdroxyacet yl-amino) -3-oxa -pentane; - 1,5-bis-(N-(3,5-bis-(N,N-bis(2-hydroxyethy1iaminocarbonyl)-2,4,6-trilodo-pheny1)-N-hvdroxyacet yl-amino)-3t.h i a-pent ane .
In compounds of formula I, Acyl preferably is a 2-'nydroxyalkanoy 1 group. Acyl-N(R)- in turn preferably represents a hydroxy ace t y 1 ami no , c(-h v d roxy p rop i ony 1 am ι no , N-mer'nyl-hydroxyacety lami no , L-N-methyl- -hydroxypropionylamino, N-ethy 1 -hydroxyacety 1 am i no , N-et hyl - 0( -hydroxy12 propionylamino, Λ-hydroxybutyrroylamino, N-methyl-A-hydroxybutyrroylamino, N-2-hydroxyethyl-hydroxyacetylamino, N-2,3-dihydroxypropyl-hydroxyacetylamino, N-l,3-dihydroxyi sopropyl -hydroxy acetyl ami no-N- 2 -hydroxy- 3 -methoxypropyl -hydroxy acetylamino , N-2-hydroxy-3-ethoxypropylhydroxyacetylamino, N-2-methoxyethyl-hydroxyacetylamino, N-2-ethoxyethy1-hydroxyacetylamino, N-2-hydroxyethyl- Λ h y dr oxy propiony lamino, N-2-hydroxyethyl-N- (X , β-di hydroxypropionylamino group.
Acyl may also be an unsubstituted or an alkoxysubstituted alkanoyl group, preferably an acetyl group, in such case R necessarily carrying a hydroxy group.
Some examples of possible substituents in -position are the following: N-2-hydroxyethyl-acetylamino, N-2-hydroxyethyl-propiony1amino, N-2-hydroxypropyl-acetylamino, N-2-hydroxy-3-methoxypropyl-acetylami no, N-2-hydroxyethy1-methoxyacety1amino.
R may also be a polyoxyethylene group of formula: H{OCH CH ) -, Me(OCH CH ) -, or Et(OCHCH). -. 2 2-5 .2 2 2-4 2 2 2-4 Y in compounds of formula I, II and III may be: hydroxy, alkoxy or hydroxyalkoxy, as for example methoxy, ethoxy, 2-hydroxyethoxy, 2,3-dihydroxypropoxy, 1,3-dihydroxyisopropoxy, or alkylamino such as methylamino, or preferably a hydroxyalkylamino group of formula : It Alkyl(OH) n wherein R , Alkyl and n have the above mentioned meanings.
Examples of such group are the following ones: 2-hydroxyethylamino, 2-hydroxypropylamino, 2,3-dihydroxypropylamino, 1,3-dihydroxyisopropylamino, 1, 3-dihydroxy-2-me thy 1-isopropy lamino, 2,3,4-trihydroxy-1-butylamino, 1,3,4-trihydroxy-2-butylamino, 1,3-dihydroxy-2-hydroxyme thyl-isopropylamino, N-methyl-N-2-hydroxyethyl ami no, N-methyl-N-2,3-dihydroxypropylamino, N-methy1-N-l,3-dihydroxyisopropylamino, N-2-hydroxyethyl-N-2,3-dihydroxypropylamino, N-2-hydroxyethyl-N-1,3-dihydroxyisopropylamino, N,N-bis-(2-hydroxyethy1) ami no, N,N-bis-(2,3-dihydroxypropyl ) amino, N,N-bis-(1,3-dihydroxyi sopropy1) amino.
Z substituent in 3-position is preferably equal to -CO-Y in 1-position, but may also be a hydroxyalkylaminocarbonyl group of formula: XR -CO-N Alkyl(OH ) n wherein R, Alkyl and n have the above mentioned meanings.
Z can also be an acylamino group, such as acetylamino, propionylamino, or a hydroxyacylamino group, such as hydroxyacetylamino, ^-hydroxypropionylamino, or a N-alky1-acylamino group, such as N-methyl-acet.ylamino, N-methyl-hydroxyacetylamino, or a N-hydroxyalky1-acety1amino group, such as N-2,3-dιhydroxypropy1-acetylam mo , N-l, 3-dihydroxy i sopropy l-acet.y lami no , N-2-hydroxyethy 1-hydroxyacety lami no, or an acylaminomethyl group, such as acetylaminomethyl or hydroxyacetylaminomethyl of formula: HO-CH -CONH-CH 2 2 In the starting compounds of formula II, the substituent in the 5-position is an aminocarbonyl-alkoxy or 5 alkylaminocarbonyl-alkoxy group, of which the following examples are reported: aminocarbony1-methoxy 1-aminocarbonyl-ethoxy me thylaminocarbony1-methoxy 10 1-(methylaminocarbonyl )-ethoxy ethylaminocarbony1-methoxy 1-(ethylaminocarbony1)-ethoxy (2-hydroxyethylaminocarbony1)-methoxy 1-(2-hydroxyethylaminocarbonyl) 15 ethoxy (2-methoxyethylaminocarbony1)-methoxy 1-(2-methoxyethylaminocarbonyl) ethoxy 1-( methylaminocarbonyl ) -2-methoxy20 ethoxy 1-( methylaminocarbonyl ) -2-ethoxyethoxy (2,3-dihydroxypropylaminocarbony1) methoxy (2-hydroxy-3-methoxy-propylaminocarbonyl)-methoxy In the starting compounds of formula III, the substituent in 5-posit.ion is an acvlamino-alkoxy group. That makes it possible to prepare a compound of formula I, in which Acyl has no hydroxy groups, in such case R NHCOCHO2 2 NH^COCH( Me )0MeNHCOCH O2 MeNHCOCH(Me)0EtNHCOCH2 0EtNHCOCH(Me JOHOCH CH NHCOCH 02 2 2 HOCH2CH2NHCOCH( Me )0MeOCH CH NHCOCH O2 2 2 MeOCH CH NHCOCH(Me )02 2 MeNHCOCH(CH OMe)0MeNHCOCH(CH OEt)0HOCH2CH{OH)CH2NHCOCH2OMeOCH CH(OH)CH NHCOCH 02 2 2 necessarily carrying a hydroxy substituent. Since said hydroxy groups are desirable, because of their ability to increase water-solubility, also both Acyl and R can be substituted by said functional groups.
According to what hereinabove stated, non limitative examples of the group of formula Acyl-NH-CH^CH(R )-O- in compounds of formula III, in which R and Acyl are as above defined, are the following ones: 2-acetylamino-ethoxy 2-hydroxyacetylamino-ethoxy 2-acetylamino-propoxy AcNHCH CHO2 2 HOCH CONHCH CH O2 ,.22 AcNHCH(Me)CH2O2-acetylamino-1-( methoxymethyl) ethoxy AcNHCH2CH(CH20Me)0HOCH( Me )CONHCH^CHOAcNHCH2CH(Me JOMeOCH CONHCH CH O2 2 2 MeOCH^ONHCH^HiCH OH)O2- -hydroxypropionylamino-ethoxy 2-acety1amino-1-methyl-ethoxy 2-methoxyacetylamino-ethoxy 2-methoxyacetylamino-1-hydroxymethylethoxy According to the general definition of formula I, by means of the process of the present invention, , UJ-bis-( N-2 , 4,6-t.r i iodo or tribromo-pheny 1-N--hydroxyacyl-amino ) alkanes of formula VI CH-OH CH-OH X X where i n: X, Y and Z have the same meanings of formula I, Alkylene is a straight or branched C^-C^ alkylene residue, which in turn may be substituted by hydroxy groups and/or interrupted by 0, S, SO or so2, R is H or a C^-C^ alkyl, hydroxyalkyl, alkoxyalkyl or alkoxy-hydroxyalkyl group, can also be prepared.
The above said compounds of formula VI are obtained by a double rearrangement from the corresponding bis-{N-(2,4,6-triiodo or tribromo-phenoxyacyl)-amino )-alkanes of formula VII VII wherein Y, Z, formula VI. and Alkylene have the same meanings as in of formula VIII, by a the corresponding or tribromo-benzoic acid be prepared, according to From the 3,5-bis-ethers double rearrangement, 3,5-bis-acylamino-2,4,6-triiodo derivatives of formula IX can the following scheme: v OH X R / [ \ CO-CH-R I 1 OH IX z wherein X, Y, R and R have the same meanings as in formulae I and II, respectively.
From the 3,5-bis-ethers of general formula X, by double rearrangement., the corresponding 3,5-bis-acy1amino-2,4,6-triiodo or tribromo-benzoic acid derivatives of general formula XI can be prepared, according to the following scheme: X, wherein X, Y, Acyl and have the same meanings as in formulae I, II and III, respectively.
By means of the process of the present invention, the 3 , 5-bis-acylamino-2 , 4,6-t.r i iodo or tribromo-benzoic acid derivatives of general formula XIII, can also be prepared by rearrangement of the corresponding compounds of formula XII, according to the following scheme: CO-Y X XIII, wherein : X and Y have the same meanings as in formula I , A and B, which may be the same or different , are groups of formula -N(R)CO-CHOH-R or -N(Acy1)CH^-CHOH-Rrespectively defined as in formulae IX and XI, B* is a group of formula -CH(R )CONHR or -CH(R )CH -NH-Acyl respectively defined as in formulae VIII and X .
Starting compounds necessary to carry out the synthetic process according to t.he invention are 5-( alkylaminocarbonyl-alkoxy )-2,4,6-t.r i iodo or tribromo20 benzoic acid derivatives of formulae II or VII, 5-(acylamino-alkoxy)-2,4,6-triiodo or tribromo-benzoic acid derivatives of formula III, 3,5-bis-(alkylaminocarbonyl-alkoxy ) -2 , 4 , 6-triiodo or tribromo-benzoic acid derivatives of formula VIII,3,5-bis-(acylamino-alkoxy)-2,4, 6-triodo or tribromo-benzoic acid derivatives of formula X, 3-(alkylaminocarbonylalkoxy or acylaminoalkoxy)-5-acylamino-2,4,6triodo or tribromo-benzoic acid derivatives of formula XII .
By means of known synthetic methods, the above cited 5-hydroxy-2,4,6-tr iodo or t r ibromo-benz'o'ic acid ether derivatives of formulae II, III, VII, VIII, X and XII are generally more easily obtainable than compounds of formula I.
The more evident advantage of this new synthetic process resides in that the above said contrast agents can be usually prepared more easily and in a shorter way, when compared to known methods.
In order to prepare non-ionic contrast agents, generally consisting in 5-^hydroxyacylamino or 5-(hydroxyaIkylacylamino) -2,4,6-1riiodo or tribromobis-( hydroxy-alky1)isophthalamides, by means of known synthetic methods, the proper intermediates are usually subjected to acylation and/or alkylation at. the aromatic nitrogen in 5-pos it ion, thus obta i n ing the corresponding anilides and/or alkylani1 ides . An undesired even if partial reaction of the hydroxy groups present in t.he molecule with the acylating or t.he alkylating agent, to give the corresponding O-acetyl or O-alkyl derivatives, is in such way inevitable. This makes the purification of t.he the use of preserve the process of protecting alkylating final products quite difficult, or requires appropriate protecting groups, in order to hydroxy groups from said side reactions. By the the invention, on the contrary, the use of such groups is no more necessary, since acylating or agents are not used.
Synthetic schemes illustrating respectively the process of the invention (Fig. No. 1) in comparison with a known synthesis of Ioversol (Fig. No. 2, USA Pat. 4.396.598) are hereinbelow enclosed as an example. .
The above said advantages of easiness and shortness of the synthesis, besides the ones deriving from avoiding the use of dangerous and polluting reactants, such as thionyl chloride, or large amounts of acetic anhydride and soda to protect and subsequently deprotect hydroxy groups, are immediately evident from a comparative examination of the two processes.
Another favourable aspect of the process resides in the remarkable easiness of t.he purification steps, because of the minimum amounts of salts to be removed, while, using known synthetic met.hods, long and expensive separation techniques are required in order to remove large amounts of such Up to now, compounds of formula disclosed .
Only a merely Smiles rearrangement. differences exist even examples of said react. impu r 11.1 e s . such rearrangement reactions of le II and III have never been formal comparison may be done with reaction, although remarkable in comparison with the most similar ι on .
In this respect, see the following enclosed references : W. E. Truce et al, Organic Reactions 18, 99-215 (1970); J.F. Bunnet et al, Chemical Reviews 49, 362 (1951); G.G. Wubbels et al, J .Amer.Chem.Soc. 102,4848,4849(1980) E.A. Nodiff et al, J. Org. Chem. 29 , 2453-2455 (1964); G.E. Bonvicino et al, J. Org. Chem. 27 , 4272-4280 ( 1962 ) ; W.R. Baker, J. Org. Chem. 48 The rearrangement reaction can , 5140-5143 (1983). be carried out in water or in an organic solvent’ such as methanol, ethanol, isopropanol, 2-methoxyethanol, 1,2-dimeth'oxye thane , 1,2-propanediol, tetrahydrofuran (THF), benzene, toluene, pyridine or dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMAC) or hexamethylphosphoramide (HMPT), generally in the presence of only catalytic amounts of bases.
Alkali, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, alkali metal carbonates (Na^CO^, ), alkali metal hydrogenocarbonates (NaHCO^, KHCO^), alkali metal borates such as borax or sodium borate, and corresponding buffer mixtures, alcoholat.es such as sodium ethylate, sodium methylate, potassium ethylate, potassium methylate, potassium tert-but.y late, tertiary amines such as triethylamine, tributylamine, N-methyl-morpholine, N-methy 1-pyrrolidine, N-methyl-piperidine, quaternary ammonium hydroxides such as t.et. ramet.hyl ammon i um hydroxide, tet.raethylammonium hydroxide, tet.rabutylammonium hydroxide, retrabuty1ammonium fluoride, benzylt.rimety lammonium hydroxide, diazabicycloundecene (DBU), and tetraazacyclododecane (TAZA) can be used as bases .
Bases such as sodium amide and potassium amide, as well as alkali hydrides such as sodium hydride or potassium hydride, can also be considered as potentially useful.
Sometimes addition of crown ethers can also be useful to remarkably increase the reaction rate.
Reaction temperature may generally range from 0° to 150°C, preferably from 50° to 100°C; it strongly depends on the kind of solvent and base used; for example, in presence of sodium hydride or, even better, of'potassium hydride, the reaction proceeds in an aprotic solvent such as DMF or DMAC at a very high rate at. 0°C or even at lower temperatures .
Favourable conditions to increase reaction rate are attained carrying out the reaction in the presence of an alkali hydride in an ether, such as 1, 2-dimet.hoxyethane, THF, or in an aprotic solvent., adding a crown ether such as 15-crown - 5- (=1,4, 7, 10, 13-pent aoxacyc lopent.adecane ) , 18-crown-6 (=1,4,7,10,13, 16-hexaoxacyc looc t.adecane ) .
Fig- 1 © Θ © © © R NH ' ι CH^Of/o. -f-XCHCCOR.
© Fig· 2 COOH 4~ COOH © 4- 5°¾ ra 4M NCW.CH-CH, Λ | J OH OH © 4- Act°/P» X -X H0CHCOH_l_ t i I Θ ch cas ι -> CH/O/HCOH SOC2, CH^cd C H^COCi. -b OAc Fig. 2 (following) No. OH CtC CMjOH co »<κΟΗ^οηΟη<:»ϋ>μ Oh o UMC«^CWOHCKyOK TOf ·' © COHUC^Ci'oHCMjCn EXAMPLE 1 (S)5-/(2-hydroxypropionyl)-amino/-2,4,6-tri iodo-bis-(1,3 — dihydroxy isopropyl)isophthalamide. (Iopamidol). g of (S) 5-( 1-aminocarbony 1-et.hoxy ) -2 , 4-6-tr i iodo-bis(1,3-dihydroxyisopropyl ) isophtalamide (0,0141 mole) were dissolved in 110 ml of DMF. 3,6 ml of a 4 M solution of CH^ONa in CH^OH (0,0144 mole) were dropped therein at. room temperature. The reaction was complete after 65 hours (T.L.C. control: silica gel Merck plate 60F /Eluent. = CHC1 6, CH OH 3, NH OH 25% 1. Developer: starch (254 3 4 nm ) ) .
The reaction mixture 4M (3.6 ml; 0,0144 mole) salts, evaporated under was neutralized with HCl/CH^OH and, after filtration of the reduced pressure.
The crude product was solidified by treatment with CH^Cl^ then, after filtration, was dissolved in water, percolated on Amberlite IR120 and Dualite A30B and eluted with water. The neutral aqueous layer was evaporated and the crude compound was crystallized from absolute ethanol. 9.5 g of ( S) - 5/(2-hydroxypropionyl)-aminq/-2,4,6triiodo-bis (1,3-dihydroxyisopropyl)isophthalamide (0,0122 mole) were obtained.
Yield 86.6% m.p. 297°C HPLC purity 99.4% /~°(_7?P, = -139,08° (c = 1,25% as cupric complex): (theor. 3 6 ,,-143°C).
Optical purity: 97.2% Elemental Analysis Calc . % : C 26.28; H 2.85; I 48.99; N 5.41 Found % : C 26.27; H 2.85; I 48.91; N 5.36 IR;XH and C NMR spectra were in agreement with the proposed structure • A) Preparat. ion of R-5-(1-aminocarbony1-ethoxy )-2,4,6- tri iodo-bis-(1,3-dihydroxyisopropyl)isophthalamide . 35 g of R-5-( 1-et.hoxycarbonyl-ethoxy )-2,4 , 6-tr iiodo-bis-(1,3-dihydroxyisopropyl )isophthalamide (0.0434 mole) (Eur. Pat. Appl. 185130) were heated to 80°C under pressure in NH /CH OH 7N (0.63 mole) 3 j for 2.5 hours. Then the reaction mixture was evaporated to dryness and the resulting product was crystallized from absolute ethanol to give the desired product. g of R-5-( 1-aminocarbony 1-et.hoxy )-2,4,6-tr i iodo-bis - ( 1, 3-dihydroxyisopropyl )isopht. halamide ( 0.0296 mole) were obtained.
Yield: 68.2% ; m.p Elemental Analysis 110° HPLC purity 99.7%.
Calc. % : C 26.28; H 2.85; I 48.99; N 5.41 Found % : C 26.78; H 2.91; I 48.63; N 5.32 IR; and ^^C NMR spectra were in agreement with the proposed structure.
EXAMPLE 2 S-5-/72-hydroxypropionyl )methylaminq7-2,4,6-triiodo-bis( 1,3-dihydroxyisopropyl)isophthalamide.
According to the procedure of example 1, 39 g of S-5-(1-methylaminocarbonyl-ethoxy )-2,4,6-triiodo-bis-(1,3dihydroxyisopropyl )isophthalamide (0.0493 mole) in 390 ml of DMF were reacted with CH^ONa/CH^OH 4 M (12.3 ml; 0.0493 mole) at room temperature complete (T.L.C. control: When the conversion was silica gel Merck plate 60 F254/E1Uent CHC1, 6; CH OH 3; NH OH 25% 1), the reaction 3 3 4 mixture was worked as described in example 1, to give the desired compound. 27.5 g of S-5-/T2-hydroxypropionyl)methylaminq72,4, 6-t.riiodo-bis-( 1, 3-dihydroxyisopropyl) i soph thal ami de (0.0347 mole) were obtained.
Yield: 70.4%; m.p. 250°C.
Analysis : Calc. %: I 48.12 Found % : I 4 7.99 EXAMPLE 3 -(N-2-hydroxyethyl-N-hydroxyace tyl-amino)-2,4,6-triiodobis-( 2,3-dihydroxypropyl)isophthalamide. ( I oversol ). 17.4 g of 5-(2-hydroxyethyl)-aminocarbonylmethoxy2,4,6-tri iodo-bis-(2,3-dihydroxypropyl)isophthalamide (EP-A-0 . 185 . 130 , Ex. 31) (0.0216 mole) were heated to 90°C in 375 ml of water.
The pH of the solution was adjusted to 9 by addition of 0.05 N NaOH and the reaction was monitored by T.L.C. After 5 hours, about 70-75% of the starting compound was transformed into the final product. After neutralization with 0.05 N HC1, solvent was concentrated; upon cooling the major part of the unreacted smarting compound crystallized and was filtered off.
The filtrate containing the title compound was made free from salts by ion-exchange resins. The final crude product was eventually purified on Amberlite XAD-2. 11.91 g of the desired compound were obtained (0.0148 mole). Yield 68% ; m.p.: 195°C ; HPLC Purity: 99% .
The characteristics of the obtained compound were in agreement with those of the derivative described in EP-A-0.083.964.
EXAMPLE 4 -(14-2 , 3-dihydr ox ypropyl-N-hydroxy acetyl- amino )-2,4,6-triiodo-bis-(2, 3-d i hydroxypropy1)i soph thalamide. g of 5-(2,3-dihydroxypropyl)aminocarbonylmethoxy-2,4,6-triiodo-bis-(2,3-dιhydroxypropyl )isophthalamide (EP-A0.185.130, Ex.: 32) (0.0251 mole) were heated to 90°C in 650 ml of water. pH was adjusted to 9 by addition of 0.05 M NaOH. Disappearance of the starting compound and formation of the final one were monitored by T.L.C.
After 5 hours the reaction mixture was cooled, neutralized with 0,05 M unreacted starting compound filtrate was made free from The obtained crude product example 1. .1 g of the final HCl and concentrated. The was crystallized off, and the salts by ion-exchange resins, was purified as described in compound (0.0121 mole) were obtained.
Yield: 48% ; m.p. 195-200°.
Elemental Analysis Calc. % : C 27.26; H Found % : C 26.71; H 3.13; I 45.48; N 5.02 3.26; I 45.35; N 4.88 EXAMPLE 5 -(N-methyl-N-hydroxyacetyl-amino)-2,4,6-t.r i iodo-bis - (2,3dihycroxypropyl )isophthalamide. (Iomeprol) g of 5-met.hylaminocarbonylmet.hoxy-2,4,6-triiodo-bis-(2,3-dihydroxypropy1)isophthalamide (EP-A-0.185. 130, Ex.: 30) (0,0515 mole) were heated to 90°C in water and pH was adjusted to 9 by addition of 0,05 M NaOH. The reaction was monitored by T.L.C. After about 4.5 hours, the reaction mixture was neutralized by means of 0.05 M HCl, then the final compound was purified as described in example 1. 34.15 g of t.he final compound were obtained (0.04 39 mole ) .
Yield: 85% m .p. 280-282°C, with decomposition. Elemental Analysis Calc. % : C 26.27; H 2.85; I 48.99; N 5.41 Found % : C 26.18; H 2.87; 1 48.99; N 5.39 The product was cor responding to t.he one described in EP-A-0.062.281, Ex.: 9.
EXAMPLE 6 -(N-methyl-N-hydroxyacetyl-amino )-2,4,6-tri iodo-bis-(2,3dihydroxypropy1)isophthalamide. g of 5-methylaminocarbonylmethoxy-2,4,6-triiodobis- ( 2 , 3-dihydroxypropyl ) isophthalamide (0.0051 mole) in 40 ml of DMAC were mixed at 25°C with 1 equivalent of potassium hydride and 18-crown-6-( =1,4,7,10 , 13,16-hexa10 oxacyclooctadecane).
The reaction was monitored by T.L.C. After 1 hour, a conversion of about 75% was obtained. Solvent was evaporated under reduced pressure, then purification and recovery of the final compound were carried out according to the procedure described in example 1. 2.3 g of the final product were obtained (0.0033 mole ).
Yield: 64.3% m.p. 280-283°C with decomposition.
EXAMPLE 7 l,3-bis-(N-(3,5-bis-(2,3-dihydroxypropylaminocarbonyl ) 2,4,6-triiodo-phen y1)-N-hydroxyacety1-ami no )-propane . .8 c of l,3-bis-(3,5-bis(2,3-dihydroxypropylaminocarbony1)-2,4,6-t r iiodo-phenoxy-acet ylamino)-propane (obt a in25 ed according to the general procedure disclosed in EP-A-185.i30) (0.0037 mole) were suspended in 1160 ml of 0.022 M borate buffer and heated to 95°C, with constant control of pil (pH=9). A conversion of 70.22% (determinated by HPLC) was obtained aft.er about 3 hours.
Following the procedure described in example 1, t.he reaction mixture was then cooled to room temperature, made free from salts and purified to give the desired compound. 3.2 g of 1,3-bis-(N-(3,5-bis-(2,3-dihydroxypropy1aminocarbonyl )-2,4,6-triiodo-phenyl)-N-hydroxyacetyl-ami no)propane (0.002 mole), were obtained.
Yield: 54% ; m.p. 234-236°C with decomposition.
Analysis Calc. % : I 48.61 Found % : I 48.23 T.L.C. Rf = 0.27 (Eluent: butanol/AcOH/H^ = 15:3r5) HPLC; Rt = 14 minutes; Visualizer: UV (254 nm) Lichrosorb RP18 5 u - (250X4) Column Temperature: 60°C Eluent (gradient): A = ΚΗΡΟ, 0.0125 M 2 4 B = CH3CN/H2O 1/1 v/v Time (min.): 0; 5; 30; 50; % B : 1; 5; 20; 75; The general procedure followed in examples 8 to 27 to study the progress of the reaction with the change of various parameters thereof (solvent, base, temperature) is herein reported. The results are hereinbelow summarized in Table 2.
EXAMPLES 8-27 -( N-me thyl-N-hydroxy acet.yl-amino)-2, 4 , 6-t r i iodo-bis - ( 2, 3dihyaroxypropy1)isophtha1amide . -methylaminocarbonylmethoxy-2,4,6-t riiodo-bis-(2,3 dihydroxypropyl )isophthalamide was dissolved or suspended in the solvent in a reactor, provided with a refrigerant with a KOH valve and under nitrogen atmosphere, and the mixture was stirred at a temperature ranging from 25°C to 95°C. The selected base, generally in an equimolecular amount to the starting product, was added to the solution (Method A) or to the suspension (Method B).
The reaction was monitored by T.L.C. or HPLC (analytical conditions are hereinbelow specified in Table 1) and conversion percentages and reaction times were evaluated and reported in table 2.
The characteristics of the obtained 5-(N-methy1-Nhydroxyacetyl-amino )-2,4,6-tri iodo-bis-(2,3-dihydroxypropyl) isophthalamide were in agreement with those of the product described in EP-0.026.281, Ex.: 9.
TABLE 1 1) T.L.C. conditions: Support. = Merck silica gel plate 60 ^54 Eluerit. - A: chloroform 6, methanol 3, ammonia 25% i B: chloroform 70, methanol 30, acetic acid 2 C: 2-butanone 15, acetic acid 3, water 5 Developer = starch and exposition to UV 1ight (2 54 nm) . 2) H.P.L.C. conditions; Eluent, (gradient) Solvent. A = KH PO 0.0 125 M 2 4 Solvent B = H^/CH CN 85/15 (v/v) Time (min.) 0; 5; 15; 25; % B 10; 10; 8 3,5:83,5; Lichrosorb column RP-18; 5 u - (250X4 nm) Column T = 60°C Visualizer: UV (254 nm) Rt S.C.* about 12.9’ Rt E.C.* about 9.5' * S.C. = starting compound 5 E.C. = end compound TABLE 2 Ex ample N. S.C. grams* Solvent Solvent grams Base Molar ratio base/s.c. Method Reaction Temp. (°C) % of conver- sion Analyt. method Time (hrs) 8 0,25 Water 50 NaOH 0,1 A 95 92,5. HPLC 5,5 9 0,25 50 NaOH 1 A 95 95,2 HPLC 1 10 0,25 50 ISOSERINOL (a) 1 A 95 93,3 HPLC 7 11 0,25 50 DBU (b) 1 A 95 88,6 HPLC 1 12 0,25 50 TBAOH (c) 1 A 95 90,9 HPLC 1 13 0,25 50 TAZA (d) 1 A 95 93,8 HPLC 2,5 14 0,25 50 bill, OH A 40 A 95 85,8 HPLC 5 15 0,45 Methanol 39,5 NaOH/H20 1 B 70 ca 85 TLC 2,5 16 0,45 39,5 NaOH/CH^OH 1 B 70 ca 85 TLC 3,5 17 0,45 39,5 CH^ONa 1 B 70 ca 80 TLC 4,5 18 0,45 39,5 BzTMAOH (c) 1 B 70 ca 85 TLC 3,5 19 0,40 1,2-Pvcpa- rediol 50 DBU (b) 1 B 85 91 HPLC 2 20 0,30 DMF 17K2CO3 1 A 80 . 74 HPLC 0,25 21 0,50 20 DBU (b) 1 A 75 ' 85 HPLC 0,5 22 0,50 20 tert-BuOK 1 A 75 68 HPLC 0,25 TABLE 2 Example N. s .c . * grams Solvent Sol- vent grams Base Molar ratio * base/s.c Method Reaction Temp. (°C) % of conver- sion Analyt. method Time (hrs) 23 1,50 DMAC 18 Nail 1 A 55 ca 40 TLC 0,5 24 0,30 19 TBAF (f) 1 A 80 50 HPLC 2 25 0,25 HMPT (g) 67 TAZA(d)+CH3ONa 1 B 80 ca 35 TLC 3,5 26 0,25 59 CH3ONa 1 B 25 ca 50 TLC 2 27 0,25 Fyridi re 37 Py+CH-jONa 1 A 50 ca 50 TLC 0,25 ι L-J (a) Isoserinol = 2 , 3-dihydroxypropylamine ι (b) DBU = 1, 8-Diazab.icyc lo/5 , 4 , 0_/-7-undecene (c) TBAOII = Tetrabutylammonium hydroxide (d) TAZA ~ 1,4,7,1O-Tetraazacyc1ododecane (e) BzTMAOII = Benzy1trimethy1ammonium hydroxide (f) TBAF - Tetrabuty1ammonium fluoride (g) HMPT = Hexamethylphosphoryltriamide * s.c. = start.ing compound EXAMPLE 28 -(N-2-hydroxyethyl-N-hydroxyacetyl-amino)-2, 4, 6-tri iodobis- ( 2 , 3-dihydroxypropyl) isophthalate . g of 5-(N-2-hydroxyethylaminocarbonylmethoxy)-2,4,6-triiodo-bis-(2,3-dihydroxypropyl) isophthalate ( obtained according to the general procedure disclosed in EP-A-185.130) were dissolved in DMF at room temperature and added with an equimolar amount of CH^ONa/CH^OH 4 M.
The reaction was monitored by T.L.C. and gave an approximate conversion percentage of 75%, after 32 hours, at room temperature.
After evaporation of the solvent, the crude compound was worked according to the method described in Example 1, to give the desired product. 4.34 g of 5-(N-2-hydroxyethyl-N-hydroxyacet.yl-amino)-2,4,6-tri iodo-bis-(2,3-dihydroxypropy1)i sophtha late were obtained.
Yield: 62% Elemental analysis: Calc. % : C 26.7; H 2.7; I 47.09; N 1.7 Found % : C 26.2; H 3.0; I 46.95; N 2.01 By the same procedure, 5-( N-met.hyl-N-hydroxyacetyl-amino)-2,4,6-tri iodo-bis - (2, 3-dihydroxypropy 1 ) isopht.halat.e was obtained from 5-( N-methylaminocarbony lmet.hoxy )-2 , 4,6rriioco-bis-(2, 3-dihydroxypropy 1 ) isopht.alat.e (obtained according to the general procedure illustrated in EP-A-185.130) .
Yield: 70% m.p. : 104-110°C Elemental analysis Calc . % : C 26,21; H 2,59; I 48.87; N 1.80 Found % : C 25.10; H 2.64; I 47.40; N 2,02; EXAMPLE 29 -(N-1,3-dihydroxyisopropyl-N-hydroxyacetyl-amino )-2,4,6tribromo-bis-(1,3-dihydroxyisopropyl)isophthalamide. 8.7 g of 5-(1,3-dihydroxyisopropylaminocarbony1)methoxy2,4,6-tribromo-bis-(1,3-dihydroxyisopropyl)isophthalamide (EP-A-185.130; Ex. 12) were suspended in 0.025 M borate buffer (pH = 9) and heated to 95°C, keeping constant. pH. Rearrangement was monitored by NMR (following the' decrease of the signal of the aromatic C in the 5-position bound to the oxygen and the rise of the signal of the aromatic C in 5-position bound to the nitrogen atom, each of them respectively characterizing the starting and the final compound). The reaction was complete in about 18 hours, then the reaction mixture was treated according to the method described in Ex. 1, to give the desired compound. 4.26 g of 5-(N-l, 3-dihydroxyisopropyl-N-hydroxyacet.yl-amino ) - 2,4 , 6-tribromo-bi s- ( 1, 3-dihydroxy i sopropyl ) i sophthalamide were obtained.
Yield: 49% Analysis : Calc. % : Br 34.43 Found % : Br 34.28 13C NMR (Bruker AC200, provided with ASPECT 3000). Spectra were recorded in DMSO at. room temperature.
Chemical shifts of aromatic C in 5-position (referred to TMS ) : C^ bound to -OR 154.9 ppm (starting compound) bound to -N^ = 147 ppm (final compound) EXAMPLE 30 -(N-methyl-N-hydroxyacetyl-amino)-2,4,6-tri iodo-((N-2,3dihydroxypropyl) -(N'-2-hydroxyethyl))i sophthalamide . 7,47 g of 5-(methy laminocarbony 1-methoxy ) - 2 , 4,6-t.r i iodo((N-2,3-dihydroxypropyl)-(N*-2-hydroxyethy1) )ιsopht halami de (obtained according to the general procedure disclosed in EP-A-185.i30) (0,01 mole) were suspended in 75 ml of water and heated to 95°C. 15 ml of NaOH 0,05 M were added and the reaction was stirred for 1 hour. Then, after cooling, the mixture was filtered and purified on Amberlite IR 120 (1,5 ml) and Amberlite IRA 400 (3 ml).
The eluate was evaporated and the crude residue was crystallized from absolute ethanol. ,1 g of 5-(methyl-N-hydroxyacel.y 1 -amino ) -2 , 4,6-1riiodo((N-2,3-dihydroxypropyl) -(N'-2-hydroxyet hyl))isophthalamide were obtained.
Yield: 68,3% mp: 259°C HPLC purity: 93% IR; '''H and ^^C NMR spectra were in agreement, with the proposed structure.
EXAMPLE 31 1,3-bis-(N-3,5-bis-(1,3-dihydroxy i sopropylaminocarbonyl )2,4,6-1. r i iodo-phenyl ) - N-hydroxyacet y 1 - ami no ! - 2-hydroxypropane . 2,5 g of 1,3-bis(3,5-bis-(1,3-dihydroxyιsopropylaminocarbony 1 ) - 2 , 4,6-1.r i iodo-phenoxy - ace t.y 1 am ι no > - 2 -hydroxy-propane (obtained according to the general procedure disclosed in EP-A-185.130) (0,00158 mole) were suspended into 50 ml of water containing NaOH (0.0032 mole) and heated to 80°C.
The reaction was monitored by H.P.L.C.; after 3.5 hours a conversion of 80% was obtained. After cooling and neutralization, the reaction mixture was worked according to the usual way of Example 1 and the final compound was purified by preparative HPLC.
Preparative purification conditions: Column: HIBAR lichrosorb RP-8; 7 u (250 x 10) Eluent: A - Η O 2 B = t^O/CH CN 1/1 v/v Gradient: (flow: 6 ml/min.); Visualizer = 254 nm, .
T(min): 0.0; 8.0; 12.0; 28.0; 35.0; % B ; 10; 18; 18; 90; 90; 1,1 g of 1,3-bis-(N-(3,5-bis-(1,3-dihydroxyisopropylamino15 carbonyl )-2,4, 6-tri iodo-phenyl )-N-hydroxyacetyl-amino )-2hydroxy-propane were obtained.
Yield: 44% m.p. 216-222°C NMR; 33C (Bruker AC200, provided with ASPECT 3000). Spectra were recorded in DMSO at room temperature.
A; (starting compound) wherein : Z = B: ( final compound) wherein : Z ' = OH 0 II I II OH 1 A -1-1- 1 1 I 1 B 42,24 1 1 1 ©1 43,91 53,05 1 ©1 53,10 69,30 1 @1 59,42 I 68,16 1 ©1 70,15 70,19 1 ©1 71,78 • 1 87,31 1 ©1 82,78 1 90,37 1 ©1 92,40 150,46 1 ©1 151,42 156,63 1 ©I 145,31 166,54 1® 1 169,07 168,70 1© 1 172,04 1 1 1 Chemical shifts are expressed in ppm referred to TMS. HPLC; Rt = 9.65; 10.10 minutes (isomeric mixture) Lichrosorb RP-8 column; 5 u (250 x 4) Eluent: A = H2O B = H O/CH CN 1/1 v/v 2 3 Gradient: (flow: 1 ml/min) Visualizer: UV (254 nm) T (min.) = 0.0; 8.5; 12.0; 23.0; 35.0; %B = 10 ; 20; 20; 90; 90; EXAMPLE 32 1,3-bis-(N-(3,5-bis-(N,N-bis-(2-hydroxyethyl)aminocarbonyl ) -2,4,6-triiodo-phenyl)-N-hydroxyacetyl-amino)-2,2-bis-(hydroxymethyl)-propane A) l,3-bis-(chloroacetylamino)-2,2-bis-(hydroxymethyl)-propane 6.7 g of 2,2-bis-( aminomethyl)-propane-1,3-diol (obtained by a full conventional way; see: Beilstein 4 E III page 850; Ε IV page 1883) (0.05 mole) in 25 ml of methanol were dropped into a solution of -12 g of methyl-chloroacetate (0.11 mole) in 35 ml of methanol, while the temperature was kept between 0 and 5°C.
Then the temperature was allowed to raise to 20-25°C and the mixture was stirred for 20 hours, until pH became neutral.
Solvent was then evaporated and the residue was solidified under vacuum and in presence of Ρ2θ5' The crude residue was boiled three times with chloroform (3 x 40 ml) and the total organic layer was filtered and evaporated to give the desired product. 8,4 g of 1,3-bis-(chloroacetylamino)-2,2-bis-( hydroxymethyl )-propane were obtained.
Yield: 58.6% Elemental analysis: Calc. %: C 37.64; H 5.62; Cl 24.69 Found %: C 37.33; H 5.67; Cl 24.40 Β) 1, 3-bis - ( 3 , 5-bis - ( N , N-bis- ( 2-hydroxyet.hy 1) am i nocar bonyl)-2,4,6-triiodo-phenoxy-acetylamino)-2,2-bis-(hydroxymethyl)-propane 2.3 g of 1, 3-bis-(chloroacetylamino)-2,2-bis-(hydroxymethyl)-propane (0.008 mole) and 2.4 g of sodium iodide (0.016 mole) were dissolved in 20 ml of water and heated to 40°C. To the mixture was dropwise added a solution of 11.74 g of 5-hydroxy-2,4,6-triiodo-bis(N,N-bis-(2-hydroxyethyl))-isophthalamide (obtained according to the general procedure disclosed in EP-A-185.130) (0.016 mole) in 32 ml of NaOH 0.5 M (0.016 mole), then the resulting solution was heated to 80°C for 24 hours.
After cooling, the solution was diluted to 25Ω ml with water, percolated on Amberlite IRA 400 ( 60 ml) and Amberlite IR 120 (30 ml) and eluted with water.
The aqueous layer was evaporated to give the desired product. 8.1 g of crude 1,3-bis-(3,5-bis-(N,N-bis-(2-hydroxyethyl) aminocarbonyl )-2,4,6-triiodo-phenoxy-acetylamino) 2,2-bis-(hydroxymethyl)-propane were obtained.
Yield: 60.2% mp; 198°C Elemental Analysis: Calc. %: C 29-27: H 3.35; I 45.27; N 4.99 Found %: C 28.74; H 3.39; I 43.20; N 4.91 IR; H and _ ~C NMR spectra were in agreement with the proposed structure. 1,3-bis-(N-3,5-bis-(N,N-bis-(2-hydroxyethyl)aminocarbonvl-2,4, 6-tri iodo-pheny1)-N-hydroxyacetyl-amino)-2,2bis-(hydroxymethyl )- propane 3.36 g of l,3-bis-(3,5-bis-(N,N-bis-(2-hydroxyethyl)ami nocar bon yl )-2, 4-6-tri iodo-phenoxy- acetylamino) - 2 , 245 bis-(hydroxymethyl )-propane (0.002 mole) were suspended into 65 ml of water containing NaOH (0.004 mole) and heated to 85°C. Percentage of conversion was monitored by HPLC. When a conversion of 85% was obtained, the mixture was cooled and worked according to the usual way of example 1 and the desired product was purified by preparative HPLC.
Preparative purification condition: Column : HIBAR lichrosorb RP-8; 7 ^u (250 x 10) Eluent : A = HO . .
B = H2O/CH3CN 1/1 v/v Gradient : (flow: 6 ml/min); Visualizer: UV (245 nm) T (min): 0.0; 8.0; 12.0; 28.0; 35.0; % B : 10; 18; 18; 90; 90; g of 1,3-bis-(N-3,5-bis-(N,N-bis-(2-hydroxyethyl) aminocarbonyl )-2,4,6-triiodo-phenyl)-N-hydroxyacetyl-amino)-2,2bis-(hydroxymethyl)-propane was obtained.
Yield: 29.8% IR; and ^^C NMR spectra were in agreement with the proposed structure.
By the same procedure, 1,3-bis-(chloroacetylamino)-2,2bis-(hydroxymethyl)-propane was reacted with -hydroxy-2,4,6-tri iodo-((N-2,3-dihydroxypropy1) -(N'-2-hydroxyethyl ) ) isophthalamide (obtained according to the general procedure disclosed in EP-A-185.130) to give the corresponding l,3-bis-(3-(2,3-dihydroxypropylaminocarbonyl)-5-(2-hydroxyethylaminocarbonyl)-2,4,6-tr i iodo-phenoxy46 acetylamino )-2,2-bis-( hydroxymethyl )-propane , which in turn was rearranged to give the corresponding 1, 3-bis-(N-(3-(2,3-dihydroxypropylaminocarbonyl)-5-(2-hydroxyethylaminocarbonyl )-2,4,6-triiodo-phenyl)-N-hydroxyacety1 -amino)-2,2-bis-(hydroxymethyl)-propane .
IR; and NMR spectra were in agreement with the proposed structure.
By the same procedure, 1,3-bis-(chloroacetylamino)-2,2-bis(hydroxymethyl)-propane was reacted with 5-hydroxy-2,4,6triiodo-((N-l,3-dihydroxyisopropyl) - ( Ν'-2-hydroxyethyl)) isophthalamide (obtained according to the general procedure disclosed in EP-A-185.130) to give the corresponding 1,3-bis-(3-(1,3-dihydroxyisopropylaminocarbonyl ) -5- ( 2-hydroxyethylaminocarbonyl )-2,4,6-tri iodo-phenoxyacetylamino)-2,2-bis-(hydroxymethyl)-propane, which in turn was rearranged to give the corresponding 1, 3-bis-(N-(3-(1,3-dihydroxyisopropylaminocarbonyl )-5-(2hydroxyethylaminocarbonyl )-2,4,6-triiodo-phenyl)-N-hydroxyacetyl-ami no )-2, 2-bis-(hydroxymethyl)-propane . 13 IR; H and C NMR spectra were in agreement with the proposed structure.
EXAMPLE 33 , 5-bis - ( N-2-hydroxyethyl-N-hydroxy acetyl - amino )-2,4,6-t. riiodo-(1,3-dihydroxyisopropyl) benzamide . 3,2 g of 3-(N-2-hydroxyethyl-N-hydroxyacetyl-amino)5-(N-2hy droxye thy lami nocar bony lme thoxy )-2, 4,6-t. rii odo - ( 1, 3-dihydroxyisopropyl ) benzamide were suspended in DMF and added with CH^ONa/CH^OH up t.o pH - 9 . The react ion was kept at. room temperature for 48 hours, then it was worked according to the usual procedure of example 1 to give the desired compound. 1,54 g of 3,5-bis-(N-2-hydroxyethyl-N-hydroxyacetyl-ami5 no )-2,4,6-triiodo-(1,3-dihydroxyisopropyl) benzamide were obtained.
Yield: 48.1% Elemental analysis: Calc. % : C 26.76; H 2.97; I 47.21; N 5.20 Found % : C 26.32; H 2.89; I 47.31; N 5.20

Claims (13)

1. A process for the preparation of 5-acylamino-2,4, 6-triiodo or tribromo-benzoic acid derivatives of formula I Ac I. wherein : X is I or Br, with the proviso that all are the same Acyl is a C -C hydroxyalkanoy1, alkoxyalkanoyl or 2. 6 alkoxy-hydroxyalkanoyl group or a C “C^ unsubstituted alkanoyl group, is H or a C-C alkyl, hydroxyalkyl, alkoxyalkyl or 1 6 alkoxy-hydroxyalkyl group. Me(OCH CH ) - or 2 2 2-4 group of formula Et(OCH CH ) 2 2 2-4 or a H(OCH 2 CH 2 ) 2 _ 5 - Acyl / group, or ^Alky 1·η« — wherein X, Y, Z and Acyl have respectively the same meanings as in formula I and Alkylene- is a straight or branched C-C alkylene 2 o group, which in turn may be substituted by hydroxy groups and/or interrupted by O,S, SO or SO^, Y is a hydroxy, alkoxy, hydroxyalkoxy, alkylamino group or preferably a hydroxyalkylamino group of formula R / -N \ Alkyl(OH) n wherein R is H or a C^-C^ alkyl, hydroxyalkyl, alkoxyalkyl or alkoxy-hydroxyalkyl group, Alkyl is a C^-C^ straight or branched alkyl group and n = 1, 2 or 3, Z may have the same meaning of CO-Y in formula I or may be a hydroxyalkylaminocarbonyl group of formula R / -CON Alkyl(OH) n wherein R, Alkyl and n are as above defined or Z may also be a C 2~ C 5 ac yl am i no ' hydroxyacylamino, N-alkyl-acylamino, N-hydroxyalkylacylamino or acylaminomethyl group, with the proviso that at least one of the two Acyl or R groups is hydroxy substituted, said process being characterized in that 5-(alkylaminocarbony1-alkoxy)-2,4,6-triiodo or tribromobenzoic acid derivatives of formula II, or 5-(acylamino-alkoxy)-2,4,6-triiodo or tribromo-benzoic acid derivatives of formula III X and Y have the same meanings as in formula I, Z' may be the same as Z in formula I, but it may also be a group of formula R'-NH-CO-CH-OI R i or Acyl-NH-CH -CH-O 2 I R i wherein R', R and Acyl are as hereinbelow defined, R' is H or a C-C alkyl, hydroxyalkyl, alkoxyalkyl or 1 6 alkoxy-hvdroxyalkyl group or a HiOCH^CH^)^ -, Me(OCH CH ) - or Et(OCH CH ) - group, or a 222-4 222-4 group of formula X O-CK-CO-NH-AlkyleneI wherein X, Y, Z' are as above defined, is as hereinbelow defined, Alkylene- is a straight or branched C -C 2 o alkylene group, which in turn may be substituted by hydroxy groups and/or interrupted by O, S, SO or SO 2 , R^ is H or a C^-C^ alkyl, hydroxyalkyl or alkoxyalkyl group, Acyl is a C -C hydroxyalkanoyl, alkoxyalkanoy1 or 2 6 alkoxy-hydroxyalkanoyl group or an unsubstitut.ed C 2 ~C^ alkanoyl group, are subjected, in presence of bases, to a rearrangement reaction to give the desired compounds of formula I.
2. A process according to claim 1, wherein alkali, alkali metal carbonates , alkali metal alcoholates, tertiary amines or quaternary ammonium salts are used as bases .
3. A process according to claim 1, wherein the rearrangement. reaction is carried out at a temperature ranging from 20°C to 150°C, preferably
4. A process according to claim alcohols, ethers, aromatic organic solvents or mixtures thereof are solvents . from 50°C to 100°C. 1, wherein water., solvents, aprotic used as reaction
5. A process according to claim i and 4, wherein the rearrangement reaction is carried out in water or in a water-alcohol mixture, at a pH value ranging from 8 to 11.
6. A process according to claim 1 for the preparation of 5-acylamino-2,4,6-triiodo or tribromo-benzoic acid 5 derivatives of formula I wherein : Χ,Υ,Ζ and Acyl are defined according to claim 1, R is a C “C 2-hydroxyalkyl or alkoxy-2-hydroxyalkyl group.
7. A process according to claim 1 for the preparation of 5-(N-alky1-N-hydroxyacy1-amino)-2,4,6-triiodo or tr ibromo-bis-( hydroxyalky1 )-isophthalamides of formula IV IV. wherein : X, R, and -N(R) Alkyl(OH ) are defined according to claim l 1 n R is defined according to claim 6, in which process 5-(alkylaminocarbonyl-alkoxy ) -2 , 4 , 6-triiodo or tribromo-bis-(hydroxyalkyl)isophthalamides of formula II subjected to a rearrangement reaction, in presence of bases and under appropriate conditions, to give the desired compounds of formula IV.
8. A process according to claim 1 for the preparation of 5-(N-hydroxyalkyl-N-acyl-amino)-2,4,6-triiodo* or tribromo-bis-(hydroxyalkyl) isophthalamides of formiila V R* * ι CO-N- Alkyl(OH) CO-N-Alkyl (OH) l n R’ ’ V. wherein : X, Acyl and -N(R)-Alkyl (OH) are defined according to n claim 1, OH-Alkyl- is a C^-C^ 2-hydroxyalkyl or alkoxy-2-hydroxyalkyl group in which process 5-(acylamino-alkoxy) -2,4 , 6-1riiodo or tribromo-bis-(hydroxyalkyl )isophthalamides of formula III, are subjected to a rearrangement reaction, in presence of bases and under appropriate conditions, to give the desired compounds of formula V.
9. A process according to claim 1 for the preparation of d\ ,ft)-bis-(N-3,5-bis-(hydroxy-alkylaminocarbony1)-2,4,6-triiodo or tribromo-phenyl)-N-acyl-amino)-alkanes or hydroxyalkanes of formula VI. R* ι ch-oh ι R. ι CH-OH I R 1 VI. wherein: X, R , N(R) —Alky1(OH) and Alkylene- are defined according to claim 1, in which process ¢( , LO-bis-( 3,5-bis-( hy20 droxyalkylaminocarbony1)-2,4,6-triiodo or tribromo-phenoxyacylamino)-alkanes of formula VII R* ’ t R' ' I CO-N- Alkyl(OH) n CO CO ι I KN- Alkylene - NH VII. wherein: X, R , N(R)-Alkyl (OH) and Alkylene- are defined 1 n according to claim 1, are subjected to a double rearrangement reaction, in presence of bases and under appropriate conditions, to give the desired compounds of formula VI.
10. A process according to claim 1 for the preparation of 3,5-bis-(N-alky1-N-acylamino)-2,4,6-tri iodo or tribromo-benzoic acid derivatives of formula IX, by means of a double rearrangement reaction of corresponding 3,5-bis-(alkylaminocarbonyl-alkoxy)-2,4,6-triioao or tribromo-benzoic acid derivatives of formula VIII, according to the following scheme: X O-CH-CO-NH-R R VIII. X R / \ CO-CH-R I 1 OH IX. OH wherein: X,Y and R^ are defined according to formulae I 20 and II in claim 1, R is defined according to claim 6.
11. A process according to claim 1 for the preparation of 3,5-(N-alky1-N-acylamino) -2,4,6-triiodo or tribromobenzoic acid derivatives of formula XI, by means of a 25 double rearrangement reaction . of corresponding 3,5-bis-(acylamino-alkoxy) -2,4,6-triiodo or tribromo-benzoic acid derivatives of formula X according to the following scheme: X R O-CH-CH^-NH-Acyl X. XI. wherein : X, Y, R and Acyl are defined according to formulae I and III in claim 1.
12. A process according to claim 1 for the preparation of 3-(N-aIky1-N-acylamino)-5-(N-alkyl-N-acylamino)-2,4, 6triiodo or tribromo-benzoic acid derivatives of formula XIII, by means of a rearrangement reaction of corresponding 3-(N-alkyl-N-acylamino)-5-alkoxy-2,4,6-triiodo or tribromo benzoic acid derivatives of formula XII, according to the following scheme: CO-Y XII. O-B* XIII. wherein : X and Y are defined according to formula I in claim 1, A and B which are the same or different, are groups of formula -N(R)COCHOH-R^ or -N(Acy1)CH^CHOH-R^ defined as in claims 10 and 11 respectively, is a group of formula -CHiR^lCONHR or -CH(R JCH^-NH-Acyl defined as in claims 10 and 11, respectively.
13. A process for the preparation of compounds of the formula I as defined in Claim 1, substantially as hereinbefore described by way of Example.
IE151888A 1987-05-22 1988-05-20 A process for the preparation of 5-acylamino-2,4,6-triiodo- or tribromo-benzoic acid derivatives and corresponding novel 5-acylamino-2,4,6-triiodo or tribromo-benzoic acid derivatives obtained by said process IE63232B1 (en)

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Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8717625D0 (en) * 1987-07-24 1987-09-03 Nycomed As Chemical compounds
EP0410974A4 (en) * 1988-03-01 1991-09-11 Mallinckrodt, Inc. Nonionic x-ray contrast agents, compositions and methods
DE68922850T2 (en) * 1988-04-06 1995-12-21 Mallinckrodt Inc METHOD FOR PRODUCING 2,4,6-TRIIODO-5-AMINO-N-ALKYL-ISOPHTHALIC ACID.
IL90326A (en) * 1988-06-02 1993-05-13 Guerbet Sa Non-ionic triiodobenzene compounds and contrast media containing them
FR2643077B1 (en) * 1989-01-23 1991-10-31 Guerbet Sa NOVEL IODIC NON-IONIC COMPOUNDS AND CONTRAST PRODUCTS CONTAINING THEM
US5614638A (en) * 1989-11-29 1997-03-25 Bracco International B.V. Nonionic radiographic contrast agents
US5075502A (en) * 1989-12-13 1991-12-24 Mallinckrodt, Inc. Nonionic x-ray contrast agents, compositions and methods
US5191120A (en) * 1989-12-13 1993-03-02 Mallinckrodt Medical, Inc. Process for preparing nonionic X-ray contrast agents
US5019371A (en) * 1990-11-21 1991-05-28 Mallinckrodt Medical, Inc. Novel x-ray contrast agents, compositions and methods
US5356613A (en) * 1991-03-18 1994-10-18 Mallinckrodt Medical, Inc. X-ray contrast agents, compositions and methods
DE4109169A1 (en) * 1991-03-20 1992-09-24 Koehler Chemie Dr Franz WATER-SOLUBLE NON-IONIC X-RAY CONTRASTING AGENTS AND AGENTS AND METHOD FOR THE PRODUCTION THEREOF
IL110391A (en) * 1993-07-30 1998-12-06 Zambon Spa Process for the crystallization of iopamidol
IT1274027B (en) * 1994-03-03 1997-07-14 Zambon Spa PROCESS FOR THE PREPARATION AND PURIFICATION OF IODURATED CONTRAST MEANS
GB9419206D0 (en) * 1994-09-23 1994-11-09 Nycomed Innovation Ab Contrast media
GB9419203D0 (en) * 1994-09-23 1994-11-09 Nycomed Innovation Ab Contrast media
IT1271134B (en) * 1994-12-01 1997-05-26 Bracco Spa IODURATED DERIVATIVES OF BIPHENYL AND THEIR DIAGNOSTIC USE
WO1997002235A1 (en) * 1995-07-04 1997-01-23 Recordati S.A. Chemical And Pharmaceutical Company A process for preparing iopamidol by using a c1-c5 monoalkylether of a c2-c10 alkylen-glycol
IT1277339B1 (en) * 1995-07-25 1997-11-10 Bracco Spa PROCESS FOR THE PRODUCTION OF IODURATED CONTRASTING AGENTS
IT1303797B1 (en) 1998-11-27 2001-02-23 Bracco Spa PROCESS FOR THE PREPARATION OF N, N'-BIS (2,3-DIHYDROXYPROPYL) -5 - ((HYDROXIACETYL) METHYLAMINE) -2,4,6-TRIIODE-1,3-BENZENDICARBOXAMIDE.
EP1186305A1 (en) * 2000-09-07 2002-03-13 Schering Aktiengesellschaft New brominated compounds as contrast media for X-ray mammography
WO2002034712A1 (en) * 2000-10-27 2002-05-02 Takeda Chemical Industries, Ltd. Process for preparing substituted aromatic compounds and intermediates therefor
AU2008273037B2 (en) * 2007-07-12 2012-11-15 Ge Healthcare As Contrast agents
EP2093206A1 (en) 2008-02-20 2009-08-26 BRACCO IMAGING S.p.A. Process for the iodination of aromatic compounds
EP2243767A1 (en) 2009-04-21 2010-10-27 Bracco Imaging S.p.A Process for the iodination of aromatic compounds
DK2451994T3 (en) 2009-07-07 2014-01-20 Bracco Imaging Spa PROCEDURE FOR THE PREPARATION OF AN IODATING AGENT
EP2394984A1 (en) 2010-06-10 2011-12-14 Bracco Imaging S.p.A Process for the iodination of phenolic derivatives
CN107253918A (en) * 2017-07-27 2017-10-17 成都丽璟科技有限公司 A kind of new method for preparing iomeprol
KR102128423B1 (en) * 2018-09-17 2020-07-01 (주)유케이케미팜 Process for the proparation of contrast medium iomeprol
WO2023209165A1 (en) 2022-04-29 2023-11-02 Bracco Imaging Spa Process for the preparation of 2,4,6-triiodophenol derivatives

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IE34927B1 (en) * 1969-06-27 1975-10-01 Nyegaard & Co As Non-ionic iodinated x-ray contrast agents
US3660464A (en) * 1970-06-19 1972-05-02 Squibb & Sons Inc Tri-iodinated diaminobenzoic acid derivatives
BE787669A (en) * 1971-08-17 1973-02-19 Schering Ag N-METHYL-DICARBOXYLIC ACID TRIIODS ANILIDES AND THEIR PREPARATION PROCESS
DD104193A5 (en) * 1972-12-22 1974-03-05
CH583562A5 (en) * 1973-07-17 1977-01-14 Bracco Ind Chimica Spa
US4065553A (en) * 1974-05-31 1977-12-27 Laboratoires Andre Guerbet X-Ray contrast media
CH608189A5 (en) * 1974-12-13 1978-12-29 Savac Ag
US4321368A (en) * 1975-10-20 1982-03-23 Mallinckrodt, Inc. Glycosyl triidobenzoic acid derivatives
DE2629228C2 (en) * 1976-06-25 1984-10-18 Schering AG, 1000 Berlin und 4709 Bergkamen Iodinated isophthalamic acid derivatives Process for their production and their use
US4191775A (en) * 1977-12-15 1980-03-04 Imperial Chemical Industries Limited Amide derivatives
DE2852094A1 (en) * 1978-11-30 1980-06-12 Schering Ag NEW X-RAY CONTRASTING AGENTS
IT1193211B (en) * 1979-08-09 1988-06-15 Bracco Ind Chimica Spa 2,4,6-TRIIODE-ISOPHTHALIC ACID DERIVATIVES, METHOD FOR THEIR PREPARATION AND CONTRAST MEANS THAT CONTAIN THEM
IT1207226B (en) * 1979-08-09 1989-05-17 Bracco Ind Chimica Spa 2,4,6-TRIIODE-ISOPHTHALIC ACID DERIVATIVES, METHOD FOR THEIR PREPARATION AND CONTRAST MEANS THAT CONTAIN THEM.
DE3150916A1 (en) * 1981-12-18 1983-06-30 Schering Ag, 1000 Berlin Und 4619 Bergkamen N-HYDROXYAETHYLATED 2,4,6-TRIJODAMINOISIOPHTHALIC ACID-BISTRIHYDROXYBUTYLAMIDES, THEIR PRODUCTION AND THEIR CONTAINING X-RAY CONTRASTING AGENTS "
US4396598A (en) * 1982-01-11 1983-08-02 Mallinckrodt, Inc. Triiodoisophthalamide X-ray contrast agent
FR2541272A1 (en) * 1983-02-23 1984-08-24 Guerbet Sa BROMINE COMPOUNDS AND OPACIFIER PRODUCTS CONTAINING THEM
DE3429949A1 (en) * 1984-08-10 1986-02-20 Schering AG, 1000 Berlin und 4709 Bergkamen Novel non-ionic 2,4,6-triiodoisophthalic acid bisamides, process for the preparation thereof and the use thereof as X-ray contrast media
US4567034A (en) * 1984-09-07 1986-01-28 E. R. Squibb & Sons, Inc. Esters of diatrizoic acid as X-ray contrast agents

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WO1988009328A1 (en) 1988-12-01
ATE79368T1 (en) 1992-08-15
CA1327600C (en) 1994-03-08
EP0365541A1 (en) 1990-05-02
US5066823A (en) 1991-11-19
DE3873766D1 (en) 1992-09-17
IE881518L (en) 1988-11-22
AU618535B2 (en) 1992-01-02
NZ224743A (en) 1991-07-26
DE3873766T2 (en) 1993-02-11
KR890701547A (en) 1989-12-20
AU1797888A (en) 1988-12-21
EP0365541B1 (en) 1992-08-12
JPH02503556A (en) 1990-10-25
ES2006951A6 (en) 1989-05-16
IL86450A0 (en) 1988-11-15
JP2585087B2 (en) 1997-02-26
KR960016747B1 (en) 1996-12-20
IL86450A (en) 1994-05-30

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